Download document 8879522

Copyright ERS Journals Ltd 1997
European Respiratory Journal
ISSN 0903 - 1936
Eur Respir J 1997; 10: 2630–2637
DOI: 10.1183/09031936.97.10112630
Printed in UK - all rights reserved
PHARMACOLOGICAL REVIEW
New immunosuppressive regimens in lung transplantation
N. Briffa*, R.E Morris**
New immunosuppressive regimens in lung transplantation. N. Briffa, R.E Morris. ©ERS
Journals Ltd 1997.
ABSTRACT: Survival after lung transplantation is less than 50% after 5 yrs and
is limited by infection and obliterative bronchiolitis. There is, therefore, a need
for new immunosuppressive regimens if we are to attempt to improve long-term
survival. Several trials in lung transplantation of new immunosuppressive agents
are in the planning stages.
In this article, we review the experience with a new monoclonal agent (interleukin 2 (IL2) receptor antagonist) in kidney transplantation, together with the
pharmacokinetic (PK) and pharmacodynamic properties and experience in transplantation in general, of the more promising of the new xenobiotic compounds
(cyclosporine microemulsion, mycophenolate mofetil, tacrolimus and sirolimus).
Recent novel approaches to the vexing problem of resistant lung rejection and
obliterative bronchiolitis, such as the use of aerosolized cyclosporine, methotrexate, total lymphoid irradiation and phototherapy, are discussed. Finally an immunosuppressive regimen, using these new drugs in lung transplantation is suggested.
Eur Respir J 1997; 10: 2630–2637.
Although the first lung transplants were performed in
the late 1960s and early 1970s, it was not until after the
introduction of cyclosporine in 1979, that improved, but
limited, clinical success was achieved in 1981 [1] when
the first heart-lung transplant was performed.
Despite being an acceptable form of therapy in the
treatment of patients with end-stage lung disease, its full
potential has not been realized for the following reasons:
1) donor organ shortage which affects lung transplantation more acutely than any other solid organ because
of the frequency with which lungs become unsuitable
for transplantation after brain death. Xenotransplantation may solve this problem; and 2) the 5 yr actuarial
survival after heart, single or double lung transplantation is still less than 50% [2].
There have been improvements in the 30 day mortality rate [2] because of advances in surgical technique
and methods of lung preservation. After 30 days, the
patient survival curves of the 1988–1991 and of the
1992–1995 eras are parallel. The main cause of death
between 30 days and 1 yr is infection and after 1 yr the
main cause of death is obliterative bronchiolitis (OB).
This fibroproliferative disorder develops in small airways of at least 50% of patients who survive for longer than 3 months after transplantation [3]. A fibrotic
repair process occurring after chronic airway injury is
the probable pathogenesis of OB [4].
Many retrospective studies have shown acute lung
rejection to be a very significant risk factor for the development of OB [3, 5, 6]. As infection is still an important cause of death after lung transplantation, further
advances in patient survival will prove to be difficult with
current immunosuppressive regimens consisting of cyclosporine, azothioprine, steroids and cytolytic agents. There
Transplantation Immunology, Dept Of
Cardiothoracic Surgery, Stanford University
School Of Medicine, Stanford, USA
Correspondence: R.E Morris, Transplantation Immunology, Dept of Cardiothoracic
Surgery, Stanford University School of
Medicine, 300 Pasteur Drive, Stanford,
CA 94305-5247, USA
Keywords: Immunosuppressive drugs
lung transplantation
Received: July 7 1997
Accepted after revision July 13 1997
NB was supported by Ethicon Foundation
grant of the Royal College of Surgeons
and the Sandoz study grant of the European
Society of Transplantation and EM by the
Ralph and Marion Falk Medical Trust and
the Hedco Foundation.
is, therefore, an urgent clinical need for more effective
and safer immunosuppressive therapies in lung transplantation.
In the last 5 yrs a number of small molecule drugs
with immunosuppressive properties have been developed (fig. 1). A few have reached the clinical arena and
have proved themselves to be promising alternatives to
the current cyclosporine based triple therapy in kidney
and liver transplantation.
The immunosuppressive efficacy of the clinically proven drugs is remarkable, considering that only one of
them (FK506) was intended from its inception to be
used as an immunosuppressant. All the other compounds
had been previously identified from discovery programmes seeking new antibiotics or antitumour drugs.
Cyclosporine
Tacrolimus
Antigen
presentation
Sirolimus
(rapamycin)
Mycophenolate
mofetil
Cytokine
secretion
Cell activation via
signalling pathways
G0 phase
T-cell
G1 phase
S phase
T and B-cells
Fig. 1. – Simplified schematic diagram for sites of action of new
xenobiotic immunosuppressive drugs. G0: quiescent phase of cells
leaving the mitotic cycle; G1: presynthetic gap (phase of cells prior
to deoxyribonucleic acid (DNA) synthesis) S: DNA synthesis leading to cell replication.
NEW IMMUNOSUPPRESSIVE REGIMENS IN LUNG TRANSPLANTATION
Induction agents
Although two recent reports have suggested that lung
transplantation without induction agents is possible without an increased rejection rate [7], polyclonal and monoclonal induction agents such as anti-thymocyte globulin
(ATG) and murine monoclonal antibody to CD3 (OKT3)
are almost uniformly used in lung transplantation. Profound T-cell depletion is one of many reasons for both
their efficacy and the effects of over immunosuppression
such as infection and malignancy. OKT3 also causes a
clinically significant cytokine response.
An induction agent that does not deplete T-cells, is
currently undergoing phase III studies in renal transplantation. It is a monoclonal agent directed against the
α chain of the interleukin (IL)-2 receptor. A randomized study in 1990 [8], comparing a rat monoclonal directed against the human Tac chain of the IL2 receptor
rabbit antithymocyte globulin (RATG) in recipients of
first time renal transplants, showed no difference in
patient or graft survival or incidence of rejection at 90
days. Thirty two per cent of patients receiving RATG,
however, had to discontinue therapy because of sideeffects whereas all patients tolerated treatment with monoclonal antibody. The patients receiving monoclonal
antibody also suffered significantly fewer infectious
episodes.
A humanized anti-Tac antibody (HAT) was recently
evaluated in 12 renal transplant patients on triple immunosuppressive therapy [9]. Whilst 41% of historical
controls had suffered an acute rejection episode in the
first year, only one patient in the lowest HAT treatment
arm had a reversible rejection episode in the same period. None of the patients receiving HAT had an infectious episode or malignancy and there were no changes
in absolute counts of CD3 cells or T-cell subsets.
Cyclosporine A (microemulsion formulation)
Background
Cyclosporine microemulsion formulation (MEF) is the
third generation derivative of cyclosporine which was
renamed from cyclosporin A by the US adopted name
council (USAN). Cyclosporine MEF (Neoral) is a newly
formulated version designed to increase the solubility
of cyclosporine in the small bowel, which is where it
is absorbed. Cyclosporine in soft gel caps (SGC) is distributed after ingestion, in oily droplets that are emulsified and digested before the drug is absorbed.
The increased solubility of cyclosporine MEF ensures
enhanced absorption through the small bowel mucosa
and reduces bile dependence and the effects of food on
absorption, thus decreasing intra- and interpatient blood
level variability.
Pharmacokinetics
The pharmacokinetics of cyclosporine MEF administered to human volunteers and stable renal and lung
transplant patients, including patients with cystic fibro-
2631
sis [10, 11] differs from cyclosporine SGC in the following ways [12]: 1) shorter time to maximum blood level
(tmax); 2) a higher maximum blood level (Cmax); 3) a
higher area under the time/concentration curve (AUC);
and 4) lower intrasubject variability for tmax, Cmax,
minimum blood level, AUC and percentage peak-trough
fluctuation.
Cyclosporine MEF shows a better correlation between
trough concentrations and AUC. Furthermore, a recent
paper has shown that in heart transplant patients, drug
levels 2 h after dosing (t2) correlate better with AUC
than trough levels (t0) [13].
Studies of the pharmacokinetics of cyclosporine MEF
in lung transplant patients have confirmed an improvement in the exposure of these patients to cyclosporine
during multiple oral dosing. This improvement is achieved without an increase in toxicity. This improvement
does not, however, fully reverse the high dosage requirements of patients with cystic fibrosis [14]. Although
data about rejection rates in lung transplant patients are
not available, in a blinded randomized study comparing
cyclosporine MEF with the older formulation in renal
transplantation, there were fewer rejection episodes and
fewer patients with multiple rejection episodes in the
group taking cyclosporine MEF [15]. This difference
did not reach statistical significance.
Tacrolimus
Tacrolimus (USAN for FK506) was discovered by
Kino and Gotoh of Fujisawa pharmaceuticals in 1984
[16], during a programme designed to discover and develop an alternative immunosuppressant to cyclosporine.
It is a macrocyclic lactone derived from the actinomycete, Streptomyces tsukubaensis.
Mechanisms of action and pharmacodynamics
Tacrolimus suppresses the immune system by similar
mechanisms to cyclosporine [17–19]. It binds in the
cytoplasm with FK binding proteins of which FKBP12
is believed to be the isoform most responsible for participating in immunosuppressive reactions. FKBPs are
the equivalent of cyclophilin, the cyclosporine binding
protein. Tacrolimus-FKBP complexes associate with
calcium dependent calcineurin-calmodulin complexes.
Calcineurin is a serine threonine phosphatase that binds
to nuclear factor of activated T-cells (NFAT). The combined NFAT/calcineurin complex migrates into the
nucleus where it acts as a transcription factor for the
activation of the promoter region of genes for various
cytokines. The tacrolimus-FKBP12 complex inactivates
the enzymatic activity of calcineurin ultimately inhibiting the transcription of cytokines, namely IL-2, IL-3,
IL-4, IL-5, interferon-γ (IFN-γ), tumour necrosis factor
α (TNF-α) and granulocyte/macrophage colony stimulating factor (GM-CSF). The limited amounts of calcineurin in immune cells as compared with nonimmune
cells, and the fact that calcineurin is critical to T-cell
activation, accounts for the relative sensitivity of lymphocytes to tacrolimus, which distributes and binds to
FKBPs in all cells.
2632
N . BRIFFA , R . E . MORRIS
Tacrolimus is 50–100 times more potent than cyclosporine in vitro. This is due to differences in partition
coefficients and increased binding affinity of tacrolimus
to FKBP [12]. The proliferative responses of T-cells to
alloantigens, plant mitogens and antiCD2 and CD3 antibodies are inhibited by tacrolimus. Direct cytotoxic cell
killing and stimulation of T-cells via the calcium independent CD28 pathway are both resistant to tacrolimus.
Pharmacokinetics
The peak concentration of infused tacrolimus undergoes a rapid initial decline due to distribution [20]. It
then slows down over the next 24 h after reaching distribution equilibrium. Absorption after oral administration is poor, with peak blood levels occurring 4 h after
intake. The oral bioavailability and tmax of tacrolimus
are highly variable and range 5–67% and 0.5–8 h. The
low and variable bioavailabilty of tacrolimus is caused by its transformation in the gut wall by cytochrome
P450 (CyP450) 3A4 enzymes and the counter transport
of parent drug and metabolites by p-glycoprotein (Pgp).
Unlike cyclosporine, tacrolimus is absorbed in a completely bile-independent manner. Trough blood levels (Cmin)
correlate well with AUC and with toxicity and, in kidney transplantation, with efficacy [21]. Assessment of
blood levels is critical to the use of tacrolimus because
of its narrow therapeutic index.
Tacrolimus levels are assayed using an enzyme linked immunosorbent assay (ELISA) or a microparticle
enzyme immunoassay of blood. These assays cannot distinguish between multiple metabolites of differing efficacy and toxicity. The whole-blood/plasma ratio varies
between 10:1 and 30:1 and, like cyclosporine, is temperature dependent.
Tacrolimus undergoes further biotransformation by
CyP450 and other isoenzymes in the liver, producing
metabolites that are excreted in bile.
Preclinical studies
A number of studies have investigated the efficacy of
tacrolimus in lung transplantation. HIRAI et al. [22]
showed prolonged graft acceptance in dogs after a short
course of tacrolimus in mongrel dogs. In another study
of lung transplantation in dogs, combined treatment with
cyclosporine resulted in improved survival when compared with either drug alone [23]. KOMATSU et al. [24]
showed tacrolimus as being effective in prolonging survival of hamster to rat pulmonary xenografts when combined with a short course of cyclophosphamide.
Clinical studies
Tacrolimus has been evaluated for its use in the prevention and treatment of rejection in patients with liver,
kidney, heart, lung, small bowel, pancreatic islet and
bone marrow transplants. In all studies tacrolimus was
used instead of cyclosporine. In liver transplantation,
patients on tacrolimus-based immunosuppressive regimens showed similar 1 yr patient and graft survival and
significantly less rejection and refractory rejection episodes [25]. In renal transplantation, the experience is less
extensive. In a randomized study comparing cyclosporine
and tacrolimus based regimens [26], there were less rejection episodes at 42 days in the tacrolimus group, and
at 1 yr, there was no difference in patient and graft
survival rates or in the number of acute rejection episodes or use of OKT3. Another randomized study comparing tacrolimus, mycophenolate and steroids with neoral,
mycophenolate and steroids, found less steroid resistant
rejection episodes (American Society of Transplant Physicians 1997). GJERTSON et al. [27] reviewed data from
the United Network Organ Sharing (UNOS) Kidney
Transplant Registry on 38,057 first time recipients of
cadaveric kidneys who underwent hospital discharge.
There were 544 on tacrolimus, 35,147 on cyclosporine
and 2,366 on others. The half lives of the different groups
were 8.8 yrs for the cyclosporine group, 7.7 yrs for the
others and 13.8 yrs for the tacrolimus. The authors state
that FK506 appears to be the first therapeutic agent to
significantly improve the long-term kidney graft survival rates.
In the only randomized open label controlled study
of tacrolimus in lung transplantation, KEENAN et al. [28]
randomized 133 recipients of lung transplants to either
cyclosporine A or tacrolimus based regimens. Although
nonsignificant, there was a trend to improved survival
at 2 yrs in the tacrolimus group. Similarly, there were
0.85 rejection episodes per 100 patient days in the tacrolimus group versus 1.09 for the cyclosporine group.
Of note, fewer patients in the tacrolimus group developed OB (21.7%) compared with the cyclosporine group
(35.8%; p=0.025). Recent data from uncontrolled studies presented at the annual meeting of the International
Society of Heart and Lung Transplantation [14] suggest
that tacrolimus is effective in treating persistent rejection and in slowing down deterioration in airflow that
occurs with OB.
Clinical studies have emphasized the similarities between the adverse effects of cyclosporine and those of
tacrolimus. Both are equally nephrotoxic. Tacrolimus
causes neurotoxicity (headache, tremor, insomnia), rash
with pruritis, hyperkalaemia, hypomagnesaemia, insulin
requiring diabetes and gastro-intestinal disturbances.
Tacrolimus causes less hypertension and less derangement of cholesterol/lipid levels [29]. Unlike cyclosporine,
it does not cause hirsutism and gingival hyperplasia.
Mycophenolate mofetil (MMF)
MMF (mycophenolic acid morpholinoethylester -RS61443) is a prodrug that, when hydrolysed by liver
esterases, produces the active metabolise mycophenolic
acid (MPA).
Mycophenolic acid (MPA) was initially derived from
cultures of Penicillium spp. in 1896 by GOSIO [30] and
purified in 1913. Its antibacterial and antifungal activities were recognized in the 1940s. It was not until the
1980s that NELSON et al. [31] of Syntex considered MPA
for use as an immunosuppressant in the USA as part of
their search for selective immunosuppressive agents in
the treatment of autoimmune disease. A morpholinoethylester of MPA was selected from a number of derivatives on the basis of its structure, its ability to inhibit
NEW IMMUNOSUPPRESSIVE REGIMENS IN LUNG TRANSPLANTATION
lymphocyte proliferation in vitro, its ability to inhibit
antibody synthesis in mice and its greater bioavailability when compared to MPA. In 1987, MORRIS et al. [32],
at Stanford University, decided to evaluate MPA for use
in transplantation.
Pharmacokinetics and mechanism of action
MPA is a noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). This
nicotinamide adenine dinucleotide (NAD) dependent
enzyme is the rate limiting enzyme in the de novo pathway for purine biosynthesis. The drug inhibits the type
II isoform of the enzyme [33] more potently than the
type I in lymphocytes.
Resting lymphocytes rely on the salvage pathway for
purine biosynthesis and on both de novo and salvage
pathways when activated. Therefore, MPA suppresses
T and B-cell activation more potently than other resting cells or other cells for which de novo purine biosynthesis is not essential for proliferation.
A diminished supply of guanine nucleotides results
in decreased deoxyribonucleic acid (DNA) synthesis,
allosteric feedback inhibitor of purine and pyrimidine
biosynthesis, inhibition of glycosylation of adhesion molecules [34], decreased endothelial cell inducible nitric
oxide synthase, increased apoptosis and decreased cyclin
dependent kinase activity resulting in the arrest of the
quiescent phase of cells leaving the mitotic cycle (G0)
and the presynthetic gap (phase of cells prior to DNA
synthesis) (G1).
Pharmacokinetics
The bioavailability of MPA is only 43% that of the
ester, which is highly soluble at the lower pH of the
upper gastro-intestinal (GI) tract and is absorbed more
rapidly. The liver is the primary location for esterase
mediated hydrolysis of MMF into MPA. The liver is
also the site of conversion of MPA to its primary metabolite, mycophenolate glucuronide. This inactive metabolise is excreted in the bile. Some of it is reconverted
to MPA by gut glucronidases and undergoes enterohepatic recirculation. This recirculation causes secondary
peaks to appear in the plasma 6–12 h post-dose. The
high concentrations of drug in the gut may account for
the GI side-effects.
MPA does not extensively distribute into cellular fractions of the blood and has a blood to plasma ratio of
0.6. The mean apparent half-life of MPA is 18 h. Clinical trials in renal transplant patients have shown immunosuppressive effects at doses starting at 2–3 g per day.
Clinical studies
MMF has been more extensively studied in controlled,
open labelled and blinded clinical trials than any other
immunosuppressant. In all studies, MMF has been substituted for azothioprine in triple therapy regimens.
In a pooled efficacy analysis of three large randomized, double blind, clinical studies of renal transplantation
2633
[35], two different doses of mycophenolate, 2 and 3 g,
were compared with azothioprine. At 1 yr, the results were
as follows: 1) graft survival was 90.4, 89.2 and 87.6%
in the MMF 2 g, MMF 3 g and azothioprine groups, respectively, but this difference did not reach statistical significance; 2) rejection episodes were 19.8, 16.5, and
40.8% in the same three groups with relative risk of
0.46 for the MMF 2 g group when compared to the
azothioprine group and 0.38 for the MMF 3 g group;
3) renal function was consistently better for both MMF
groups at 3, 6 and 12 months; 4) infections were more
common in the MMF 3 g group.
In a randomized study comparing MMF with azothioprine after heart transplantation, survival at 1 yr was
significantly higher in the MMF group. Intimal thickening as measured by intravascular ultrasound (IVUS),
was also significantly better in the MMF group [14].
At the 1997 meeting of the International Society for
Heart and Lung Transplantation [14], three centres reported their experience of MMF in lung transplantation.
None of the studies were properly controlled and each
contained relatively few patients. All the studies reported significantly less episodes of biopsy proven acute
rejection without a significant increase in infection. In
one paper the authors detected a significantly smaller
drop in forced expiratory volume in one second (FEV1)
in the MMF group.
GI has been the most common side-effect associated
with the use of MMF in both animals and humans. In
the tricontintental MMF renal transplantation study group
[36], abdominal pain and diarrhoea were the most common of the GI complications, both occurring with the
same frequency (31% of the 3 g dosage group). All GI
complications occurred less frequently in the 2 g dosage
group. Leukopenia occurred in the 3 g dose group and
the azothioprine group more frequently than in the 2 g
dose group. Despite the better rejection rate in both the
MMF groups, infection (specifically CMV tissue invasion) was slightly increased in only those patients taking 3 g of MMF a day.
Malignancies occurred in 9% of the MMF 3 g group,
11% of the MMF 2 g group and 7% of the azothioprine
group. Lymphoproliferative disorders occurred in 1%,
1% and <1% of the three groups (MMF 2 g, MMF 3 g,
azothioprine, respectively). Two of the five patients who
developed lymphoproliferative disorder had received
OKT3 for resistant rejection.
Sirolimus (rapamycin)
Sirolimus (USAN for rapamycin) is another microbial natural product and is produced by the actinomycete
Streptomyces hygroscopicus isolated from Easter Island
(Rapanui to its natives) soil samples. It emerged from an
antifungal drug discovery programme in the mid 1970s
directed by Sehgal at Ayerst Research in Montreal,
Canada. The antifungal properties of the drug were not
pursued when it became apparent that the drug caused
involution of lymphoid tissue. Martel subsequently
demonstrated that rapamycin suppresses experimental
allergic encephalomyelitis and passive cutaneous anaphylaxis in the rat. Structural analysis of rapamycin revealed a macrocyclic lactone. It was not until the newly
2634
N . BRIFFA , R . E . MORRIS
discovered structure of tacrolimus was found to be remarkably similar to that of sirolimus that groups at Stanford (MORRIS and MEISER [37]) and Cambridge (CALNE
et al. [38]) uncovered the potential of the drug as an
immunosuppressant.
Medicinal chemistry
Sirolimus shares with tacrolimus its origin from a
Streptomyces species and its structure. Both contain the
same tricarbonyl region consisting of an amide, a ketone
and a hemiketal. The sirolimus ring contains, in addition, a triene segment. This difference in structure accounts
for the lower stability of sirolimus in aqueous solution.
Like tacrolimus, sirolimus is hydrophobic.
blood concentrations of sirolimus metabolites exceed
those of the parent drug. These metabolites have shown
immunosuppressive activity in vitro.
The drug is extensively bound to cells in the blood,
much more so than cyclosporine or tacrolimus. Ninety
seven per cent of labelled drug is contained within red
and white blood cells. There have been few pharmacokinetic and toxicity studies in humans. Peak concentrations are reached within 2 h of oral dosing in healthy
volunteers and recipients of renal transplants [40]. Cmax
and AUC correlated well with dose, apart from the
lower dose of 3 mg·m-2·day-1 where levels in renal transplant patients were higher than expected. Elimination
half-life varied between 43.8 and 86.5 h in renal transplant patients.
Preclinical studies
Pharmacodynamics and mechanism of action
Sirolimus enters cells easily because of its lipophilicity. In the cell, the section of the ring that is identical
to tacrolimus binds to cytosolic FKBP. Although this
complex is necessary for the biological action of sirolimus, the target of the complex is not yet known. In
yeast cells, proteins called targets of rapamycin (TOR)
(sirolimus effector protein or SER in mammalian cells)
[39] have been identified, which may be the target of
the FKBP-sirolimus complex. The effects of interaction
between this complex and its target include inhibition
of protein synthesis by inhibition of a kinase (70 kDa
S6 kinase). This kinase normally acts on S6 ribosomal
protein. Sirolimus is also known to inhibit kinase activity of CDk2/cyclinE complex in yeast cells. This would
prevent the cell from progressing from G1 to DNA synthesis (S) phase. This is unlike cyclosporine or tacrolimus,
which inhibit cell cycle progression at the G0 to G1
stage.
As it interferes with events at a later stage than cyclosporine or tacrolimus, sirolimus is less efficient at
inhibiting cytokine synthesis. It does, however, inhibit
pathways that are resistant to cyclosporine or tacrolimus, namely calcium independent activation induced by
exogenous cytokines or stimulation of the CD28 pathway.
Immunoglobulin synthesis and antibody dependent
cellular cytotoxicity are also inhibited by sirolimus, albeit at a much higher concentration than that required
to inhibit T-cell activation. The antagonism of cytokine
and growth factor induced proliferation by sirolimus is
not restricted to cells of the immune system. It inhibits
smooth muscle cell proliferation and arterial intimal
thickening in animal models of chronic vascular disease
and after arterial injury by balloon catheter.
Pharmacokinetics
Like cyclosporine and tacrolimus, sirolimus is transformed in the gut wall and liver by cytochrome CyP450
and counter transported in the gut lumen by the multidrug resistance transporter Pgp. This accounts for its
low bioavailability and high pharmacokinetic variability.
Levels of sirolimus in the blood are best measured by
high performance liquid chromatography (HPLC). Whole
Extensive studies of the immunosuppressive effects
of sirolimus in rodent, rabbit, dog, pig and nonhuman
primate have been conducted. In summary, the drug has
been shown to prevent acute, accelerated and chronic
rejection of skin, heart, kidney, islet and small bowel
allografts. It is able to reverse ongoing allograft rejection and is effective in rodents in inducing alloantigen
specific tolerance. It has also been demonstrated to partially reverse the changes of chronic rejection in the aortic allograft model in the rat [14].
Rapamycin has been shown to be very effective in
controlling acute allograft rejection in lung transplantation in rodents [41, 42]. An analogue of rapamycin,
RAD (rapamycin derivative), is currently being tested
for efficacy in controlling acute allograft lung rejection
in an extensive nonhuman primate study.
In a heterotopic tracheal transplant model in rats,
sirolimus has been shown to prevent luminal narrowing
[43]. The lesion produced in this model has the histological characteristics of obliterative bronchiolitis. The
efficacy of sirolimus in controlling changes of chronic
rejection in both arterial and heterotopic tracheal transplant models, may result from a dual effect of the drug:
inhibition of lymphocyte function and suppression of
growth factor induced myofibroblast proliferation.
Clinical studies
KAHAN [44] has recently published phase II studies
in renal transplant patients suggesting that the drug is
able to decrease acute rejection rates from 40 to <10%
amongst patients taking full does cyclosporine. This improvement is achieved with a nonsignificant increase in
infectious complications. The authors of the study suggest that the drug may mitigate the need for long-term
steroid therapy.
The analogue of sirolimus, SDZ-RAD, is manufactured by the pharmaceutical firm Novartis (previously
Sandoz and Ciba). Phase I studies in renal transplant
patients suggest equivalent pharmacokinetic and toxicological properties to sirolimus. A multicentre study to
examine the pharmacokinetics, safety and tolerabilty of
SDZ-RAD in patients with and without cystic fibrosis
(CF), who are undergoing lung transplantation, has recently been started.
NEW IMMUNOSUPPRESSIVE REGIMENS IN LUNG TRANSPLANTATION
Doses up to 15 mg·m-2·day-1 of sirolimus were well
tolerated by renal transplant patients [40]. Increased
serum triglycerides and thrombocytopaenia may indicate dose-limiting toxicity.
Treatment of obliterative bronchiolitis and
refractory rejection
Obliterative bronchiolitis (OB) is the main complication limiting long-term success of lung transplantation.
It affects 35–68% of patients who survive longer than
3 months after lung transplantation [3]. In the Stanford
experience [6], the actuarial freedom from OB after
lung transplantation was 29% at 5 yrs [6]. Actuarial survival for patients with OB was 44% at 5 yrs versus 63%
for those without. Many studies have shown acute rejection to be a very significant risk factor for the development of OB [3, 5, 6, 45].
In one series reported from Minnesota [46], steroid
resistant rejection or recurrent rejection, defined as two
or more episodes of acute rejection in 6 months, occurred
in 11 patients out of a total population of 134 patients
who underwent lung transplantation. Clearly these patients are at high risk of developing clinical OB.
In recent years, several therapies for treating these
two complications of lung transplantation have emerged.
Cytolytic therapy
In a review of patients with clinical BOS (bronchiolitis obliterans syndrome), the rate of decline in FEV1
was diminished significantly after treatment with antithymocyte globulin [47].
In another study, a cohort of patients who had been
treated prophylactically with an induction course of
OKT3, had longer latency periods to the development
of BOS, when compared with those who had received
Minnesota antilymphocyte globulin [48].
Inhaled cyclosporine
Aerosolized cyclosporine was tried in 18 patients with
acute lung rejection that failed to resolve in response to
pulsed steroids and antilymphocyte globulin. Two patients
were withdrawn from the study because of intolerance
to the drug [49]. Significant improvement in histological rejection occurred in 14 patients. Measures of forced
vital capacity and FEV1 increased over time and the
incidence of acute rejection episodes fell from 2.49±0.68
to 0.72±0.3 episodes·100 days-1.
Methotrexate
Methotrexate has been used successfully for many
years to treat recurrent or resistant rejection after heart
transplantation. The use of this drug in lung transplantation has been described in two recent papers [46, 50].
In one study, methotrexate was used to treat patients
with resistant (no response to steroids or cytolytic therapy) and recurrent (two or more episodes in 6 months)
2635
rejection [46]. Ten of the 12 patients had no further
episodes of rejection during a mean follow-up period of
12.5 months.
In the other study, the use of methotrexate for the
treatment of OB was described. After commencement
of therapy, mean decline of FEV1 during the previous
12 months fell from 1.4±0.8 L to 0.1±0.2 L 6 months
after therapy [50].
Total lymphoid irradiation (TLI)
TLI was used to treat OB by DARK et al. [42] in
Newcastle in the UK. Twelve patients with OB were
treated at a mean of 2.37 yrs post transplant. Mean monthly change in FEV1 fell from 0.1861 to 0.0009 after
TLI. All the patients developed leucopenia. One patient
developed aspergillus disease, but there were no episodes of cytomegalovirus (CMV) reactivation. VALENTINE et
al. [51] reported moderate success with the use of TLI
to treat refractory lung rejection.
In another study, a retrospective analysis and comparison was made between patients who had received
TLI and patients who received tacrolimus for the treatment of OB [14]. Both were equally effective at slowing the rate of fall in pulmonary function. Survival of
patients receiving tacrolimus was 100% as compared
with 69% for the patients who had received TLI. All
the deaths in the TLI group were secondary to infection.
Photopheresis
Extracorporeal photochemotherapy is a modality that
has been recently used with moderate success to treat
refractory lung rejection and OB. The patient's mononuclear cells are treated with a psoralen and then exposed to ultraviolet light.
ACHKAR et al. [14] treated 11 patients with BOS and
deteriorating lung function with photopheresis. Five
patients had ongoing acute graft rejection. Lung function improved in four, and deteriorated in four. All
changes of acute lung rejection resolved. Three patients
died during treatment.
Conclusion
After 15 yrs of experience with lung transplantation,
the 5 yr actuarial survival after lung transplantation is
still less than 60%.
In the last 2–3 yrs, drugs and biological agents that
may have an impact on the unmet clinical need, i.e.
decreasing rejection and obliterative bronchiolitis without increasing toxicity, infection or malignancy in patients
after lung transplantation, have become available.
A number of randomized controlled studies are now
in the planning stages to evaluate many of these new
drugs. These new agents will form the basis of new
immunosuppressive regimens (fig. 2) for use in lung
transplantation that should have an impact on long-term
survival.
N . BRIFFA , R . E . MORRIS
2636
Cyclosporine MEF + (Sirolimus or MMF) +
anti IL2R± Tapering dose of steroids
Surveillance transbronchial biopsy
No rejection
10.
11.
Rejection
12.
Maintain on
cyclosporine and other
Treat with steroids
13.
Repeat biopsy
14.
Negative
Positive
Maintain on cyclosporine, Change cyclosporine to tacrolimus
other and steroids
15.
Repeat biopsy
Negative
Positive
16.
Maintain on tacrolimus + other + steroids
Cytolytic therapy or inhaled cyclosporine
17.
Fig. 2. – Flow diagram showing suggested new immunosuppressive
regimen for lung transplantation. MEF: microemulsion formulation;
MMF: mycophenolate mofetil; IL2R: interleukin 2R.
18.
References
19.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung
transplantation: successful therapy for patients with
pulmonary vascular disease. N Engl J Med 1982; 306:
557–564.
Hosenpud JD, Novick RJ, Bennett LE, Keck BM, Fiol
B, Daily OP. The Registry of the International Society
for Heart and Lung Transplantation: thirteenth official
report. J Heart Lung Transplant 1996; 15: 655–674.
Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. An
analysis of risk factors and management. J Thorac
Cardiovasc Surg 1995; 110: 4–14.
Tazelaar HD, Yousem SA. The pathology of combined
heart-lung transplantation: an autopsy study. Hum Pathol
1988; 19: 1403–1416.
Keller CA, Cagle PT, Brown RW, Noon G, Frost AE.
Bronchiolitis obliterans in recipients of single, double,
and heart-lung transplantation. Chest 1995; 107: 973–980.
Reichenspurner H, Girgis RE, Robbins RC, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1995; 60: 1845–1853.
Kriett JM, Smith CM, Hayden AM, et al. Lung transplantation without the use of antilymphocyte antibody
preparations. J Heart Lung Transplant 1993; 12: 915–923.
Soulillou JP, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of a monoclonal antibody against
the interleukin-2 receptor (33B3.1) as compared with
rabbit antithymocyte globulin for prophylaxis against
rejection of renal allografts [see comments]. N Engl J
Med 1990; 322: 1175–1182.
Vincenti F, Lantz M, Birnbaum J, et al. A phase I trial
of humanized anti-interleukin 2 receptor antibody in
renal transplantation. Transplantation 1997; 63: 33–38.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Girault D, Haloun A, Viard L, et al. Sandimmun neoral improves the bioavailability of cyclosporin A and
decreases inter-individual variations in patients affected
with cystic fibrosis. Transplant Proc 1995; 27: 2488–2490.
Mikhail G, Eadon H, Leaver N, et al. An investigation
of the pharmacokinetics, toxicity, and clinical efficacy
of neoral cyclosporin in cystic fibrosis patients. Transplant
Proc 1997; 29: 599–601.
Morris RE. New Immunosuppressive Drugs. Philadelphia, London, Toronto, Montreal, Sydney, Tokyo, W.B.
Saunders Company, 1995.
Rial MC, Frias S, Argento J, Tessler J, Casadei D.
Fermentation, extraction and chemical and biological
characterization. Transplant Proc 1997; 29: 292–293.
The International Society for Heart and Lung Transplantation 17th annual meeting and scientific sessions. London,
England, April 2–5, 1997. Abstracts. J Heart Lung
Transplant 1997; 16: 41–142.
Niese D. A double-blind randomized study of Sandimmun Neoral versus Sandimmun in new renal transplant
recipients: results after 12 months. The International
Sandimmun Neoral Study Group. Transplant Proc 1995;
27: 1849–1856.
Gotoh T, Nakahara K, Nishura T, et al. Convenience of
level of cyclosporine-Neoral at time 3 to determine the
area under curve in renal transplant. J Antibiotics 1982;
35: 1286–1292.
Sigal N, Dumont F. Cyclosporin A, FK 506 and rapamycin: pharmacologic probes of lymphocyte signal transduction. Ann Rev Immunol 1992; 10: 519–560.
Schreiber S, Crabtree G. The mechanism of action of
cyclosporin A and FK 506. Immunol Today 1992; 13:
136–142.
Wiederrecht G, Lam E, Hung S, et al. The mechanism
of action of FK506 and cyclosporine A. Ann NY Acad
Sci 1993; 696: 9–19.
Hausen B, Morris ER. Review of immunosuppression
for lung transplantation - novel drugs, new uses for conventional immunosuppressants, and alternative strategies. Clin Chest Med 1997; 18: 353–366.
Backman L, Nicar M, Levy M, et al. FK 506 trough
levels in whole blood and plasma in liver transplant
patients. Transplantation 1994; 57: 519–525.
Hirai T, Wada H, Hasegawa S, et al. The immunosuppressive effect of FK 506 on canine lung transplantation. J Thorac Cardiovasc Surg 1992; 103: 1127–1135.
Fujisawa T, Saitoh Y, Urabe N, et al. Dose study of the
immunosuppression of FK506 in canine allo-transplantation. Surg Today 1993; 23: 338–343.
Komatsu K, Youm W, Konishi H, et al. Prolonged
survival of hamster-to-rat pulmonary xenografts by tacrolimus (FK506) and cyclophosphamide. J Heart Lung
Transplant 1996; 15: 722–727.
European FK506 Multicentre Liver Study Group. Reduced incidence of acute, refractory acute, and chronic
rejection after liver transplantation with FK506-based
immunosuppression. Transplant Proc 1994; 26: 3260–
3263.
Vincenti F, Laskow DA, Neylan JF, Mendez R, Matas
AJ. One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the
U.S. Multicenter FK506 Kidney Transplant Group.
Transplantation 1996; 61: 1576–1581.
Gjertson DW, Cecka JM, Terasaki PI. The relative effects of FK506 and cyclosporine on short- and longterm kidney graft survival. Transplantation 1995; 60:
1384–1388.
Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of
NEW IMMUNOSUPPRESSIVE REGIMENS IN LUNG TRANSPLANTATION
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
tacrolimus versus cyclosporine in lung transplantation.
Ann Thorac Surg 1995; 60: 580–585.
Steinmuller TM, Graf KJ, Schleicher J, et al. The effect
of FK506 versus cyclosporine on glucose and lipid
metabolism: a randomized trial. Transplantation 1994;
58: 669–674.
Gosio B. Ricerche Batteriologiche e chimiche sulle alterazioni del mats. Revista d'Igiene e Sanita Pubblica Ann
1896; 7: 825–868.
Nelson P, Eugui E, Allison AC. Synthesis and immunosuppressive activity of some side chain variants of
mycophenolic acid. J Med Chem 1990; 33: 833–838.
Morris RE, Hoyt EG, Eugui E, Allison AC. Prolongation
of rat heart allograft survival by RS-61443. Surg Forum
1989; 40: 337–338.
Brazelton TR, Morris RE. Molecular mechanisms of
action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol 1996;
8: 710–720.
Laurent AF, Dumont S, Poindron P, Muller CD. Mycophenolic acid suppresses protein N-linked glycosylation
in human monocytes and their adhesion to endothelial
cells and to some substrates. Exp Hematol 1996; 24:
59–67.
Halloran, P, Mathew T, Tomlanovich S, Groth C, Hooftman
L, Barker C. Mycophenolate mofetil in renal allograft
recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal
Transplant Study Groups. Transplantation 1997; 63: 39–
47.
The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical
trial of mycophenolate mofetil for the prevention of acute
rejection in cadaveric renal transplantation. Transplantation
1996; 61: 1029–1037.
Morris R, Meiser B. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989;
17: 609–610.
Calne R, Collier D, Lim S, et al. Rapamycin for immunosuppression in organ allografting. Lancet 1989; 2:
227.
Sabatini D, Erdjument-Bromage H, Lui M, et al. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin dependent fashion and is homologous to yeast
cells. Cell 1994; 78: 35–43.
Brattstrom C, Tyden G, Sawe J, Herlenius G, Claesson
K, Groth CG. A randomized, double-blind, placebo-
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
2637
controlled study to determine safety, tolerance, and preliminary pharmacokinetics of ascending single doses of
orally administered sirolimus (rapamycin) in stable renal transplant recipients. Transplant Proc 1996; 28: 985–
986.
Program issue. The International Society for Heart Transplantation eleventh annual meeting and scientific sessions.
April 7–9, 1991, Paris, France. J Heart Lung Transplant
1991; 10: 133–200.
The International Society for Heart and Lung Transplantation 16th annual meeting and scientific sessions. New
York, March 15–18, 1996. Abstracts. J Heart Lung Transplant 1996; 15: S1–114.
Morris RE, Huang X, Gregory CR, et al. Studies in
experimental models of chronic rejection: use of rapamycin (sirolimus) and isoxazole derivatives (leflunomide and its analogue) for the suppression of graft
vascular disease and obliterative bronchiolitis. Transplant
Proc 1995; 27: 2068–2069.
Kahan B. Sirolimus: a new agent for clinical renal transplantation. Transplant Proceedings 1997; 29: 48–50.
Wahlers T, Haverich A, Schafers HJ, et al. Chronic
rejection following lung transplantation. Incidence, time
pattern and consequences. Eur J Cardiothorac Surg
1993; 7: 319–324.
Cahill BC, O'Rourke MK, Strasburg KA, et al. Methotrexate for lung transplant recipients with steroid-resistant
acute rejection. J Heart Lung Transplant 1996; 15:
1130–1137.
Snell GI, Esmore DS, Williams TJ. Cytolytic therapy
for the bronchiolitis obliterans syndrome complicating
lung transplantation. Chest 1996; 109: 874–878.
Ross DJ, Jordan SC, Nathan SD, Kass RM, Koerner SK.
Delayed development of obliterative bronchiolitis syndrome with OKT3 after unilateral lung transplantation.
A plea for multicenter immunosuppressive trials. Chest
1996; 109: 870–873.
Iacono AT, Keenan RJ, Duncan SR, et al. Aerosolized
cyclosporine in lung recipients with refractory chronic
rejection. Am J Respir Crit Care Med 1996; 153:
1451–1455.
Dusmet M, Maurer J, Winton T, Kesten S. Methotrexate
can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung
Transplant 1996; 15: 948–954.
Valentine VG, Robbins RC, Wehner JH, Patel HR, Berry
GJ, Theodore J. Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts.
Chest 1996; 109: 1184–1189.